Project Summary One of the main bottlenecks to therapeutic development is the rapid synthesis of complex organic molecules to evaluate for bioactivity. One of the best means of accomplishing the discovery of the next generation of therapeutics is the late stage functionalization (LSF) of lead structures, such that key properties (KD, log P, PK, PD, etc) are optimized along specific growth vectors of the core structure. Consequently, synthetic methodologies that are able to modify complex target molecules at specific aliphatic and aromatic sites either through C?H or C?O bond functionalization are ideal so as to avoid de novo synthesis of the target of interest. The aim of this MIRA grant is to merge two productive NIGMS-funded projects that broadly seek to develop new catalytic chemical transformations for immediate use in the biomedical community for rapid derivatization of complex organic molecules. More specifically, we aim to develop new catalytic methods for functionalization of aliphatic C?H bonds and aromatic C?O bonds by activation of organic substrates using potent single electron organic photooxidants. We envision that activation of typically unreactive C?H bonds can be accomplished via the catalytic generation of heteroatom radical species that is capable of selective H-atom abstraction. The resultant radicals can engage in a number of radical group transfer reactions including conjugate addition, halogenation, azidation and thiotrifluoromethylation. We aim to target unreactive primary and secondary C?H bonds by modification of the heteroatom-centered radical species. Importantly, enantioselective variants of the radical reactions herein will be explored, as few reactions of this type are known. Further elaboration of these radical transformations will allow for cascade-type reactions wherein complex chiral building blocks can be forged without the need for prefunctionalization of the starting materials. Opportunities to utilize some of these radical transformations in cascade sequences for natural product synthesis will be exploited, as in the case of stemocurtisine, a member of the stemona alkaloid family. We also will continue a program aimed at aromatic C?H and C?O bond functionalization. A novel method for catalysis of the venerable nucleophilic aromatic substitution reaction using alkoxyarenes as substrates will allow for direct substitution by amines, cyanide, fluoride and azoles with the alkoxide acting as the nucleofuge. These newly developed transformations will enable synthetic practitioners with new tools for complex molecule synthesis aimed at therapeutic discovery.